ASA: Novel Agent Cuts Stroke in Hard-to-Treat Afib

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In this double-blinded study 5,599 patients with atrial fibrillation and at least one other risk factor for stroke were randomly assigned to aspirin or apixaban, a novel factor Xa inhibitor.

All patients in this study were considered unsuitable for treatment with warfarin.

Treatment with apixaban was associated with a significant reduction in stroke and systemic embolism without an increased risk of hemorrhagic complications.

LOS ANGELES -- In patients with atrial fibrillation who can't take vitamin K antagonist therapy, the experimental anticoagulant apixaban is superior to aspirin for preventing stroke or systemic embolism, final results of the AVERROES trial confirmed.

Through about one year of follow-up, the rate of stroke or systemic embolism was 1.6% per year in the apixaban group and 3.7% per year in the aspirin group (HR 0.45, 95% CI 0.32 to 0.62), according to Hans-Christoph Diener, MD, PhD, of University Duisburg-Essen in Germany.

The rate of death was lower among patients taking apixaban (3.5% versus 4.4% per year) but this did not reach statistical significance (P=0.07). There was a significant reduction in the risk of a first hospitalization for cardiovascular causes (12.6% versus 15.9% per year, P<0.001).

The rate of major bleeding -- the primary safety endpoint -- was not raised in the apixaban group (1.4% versus 1.2% per year; HR 1.13, 95% CI 0.74 to 1.75), Diener reported here at the American Stroke Association's International Stroke Conference.

The findings, which confirm the initial results presented last year at the European Society of Cardiology meeting, were reported simultaneously online in the New England Journal of Medicine.

Diener and his colleagues noted in their paper that treating 1,000 patients for one year with apixaban rather than aspirin would prevent 21 strokes or systemic emboli, nine deaths, and 33 hospitalizations for cardiovascular causes, at the cost of two major bleeds.

"The net clinical benefit of apixaban in these patients was therefore substantial," they wrote.

Some patients are not good candidates for vitamin K antagonist therapy for numerous reasons, including an unwillingness to comply with regular testing, a proven inability to maintain an INR within the therapeutic range, a moderate risk of stroke, or a refusal to receive the therapy.

Aspirin reduces the risk of stroke for patients with atrial fibrillation, and adding clopidogrel (Plavix) reduces the risk even further, but the combination increases the risk of major hemorrhage.

Diener and his colleagues evaluated apixaban -- a novel factor Xa inhibitor -- as a treatment option for patients with atrial fibrillation who cannot take vitamin K antagonist therapy.

The AVERROES trial randomized 5,599 patients to apixaban (5 mg twice a day) or aspirin (81 to 324 mg daily) at 522 centers in 36 countries; 37% of the patients were from North America or western Europe.

In addition to unsuitability for vitamin K antagonist therapy, all patients had at least one risk factor for stroke.

The trial was stopped prematurely by its data and safety monitoring board after a mean follow-up of 1.1 years because prespecified interim analyses identified a clear benefit for apixaban in reducing stroke or systemic emboli.

The treatment effects were consistent in various subgroups, including high-risk patients who had already had a stroke or a transient ischemic attack.

Although major bleeding was not significantly increased in the apixaban group, an on-treatment analysis that included only those events occurring within two days of permanent study drug discontinuation approached significance (1.4% versus 0.9% per year; HR 1.54, 95% CI 0.96 to 2.45).

"The on-treatment analysis may provide a more specific measure of the effect of therapy but does so at the risk of introducing potential bias," the authors wrote.

There was no suggestion of an increase in intracranial bleeding -- a feared complication of antithrombotic therapy, according to the researchers -- in the apixaban group, with 11 cases in that group and 13 in the aspirin group.

"This finding, together with the report of a much lower risk of hemorrhagic stroke with dabigatran (Pradaxa) as compared with warfarin, indicates that reduction of intracranial bleeding will be one of the most important benefits of the newer oral antithrombotic drugs over vitamin K antagonist therapy," Diener and his colleagues wrote.

Serious adverse events occurred less frequently in the apixaban group (22% versus 27%), a difference mostly driven by fewer events related to vascular disorders of the central nervous system.

The authors acknowledged that early termination of the trial could have inflated the measured benefit.

AVERROES was funded by Bristol-Myers Squibb and Pfizer.

Connolly reported receiving payment for serving on the boards of Boehringer Ingelheim, sanofi-aventis, Portola, and Merck, consulting fees from Boehringer Ingelheim, sanofi-aventis, Portola, and Merck, grant support on behalf of his institution from Boehringer Ingelheim, sanofi-aventis, Portola, and Bristol-Myers Squibb, and lecture fees from Boehringer Ingelheim, sanofi-aventis, and Portola.